The broad long-term objective of this proposal is to understand how memory loss occurs in Alzheimer's disease (AD). In 2006, we have shown that a specific amyloid beta (A3) assembly that we named A3*56 was likely the cause of cognitive decline in the mouse model of AD, Tg2576. As part of the mentored phase of this award (K99), we confirmed the existence of Alphabeta*56 in the human brain tissues and cerebrospinal fluid. We measured the prominence of several oligomers including Alphabeta*56 in three clinical groups: non-cognitively impaired age-matched normals (NCI), mild cognitive impairment (MCI) and Alzheimer's disease(AD). We found that Alphabeta*56 levels rise during the 5^ decade of life during which the first signs of memory decline is noticeable (also known as AAMI) and its levels decrease with disease progression. Trimers peaked in MCI brain tissues while dimers slowly increased with dementia. In addition, we identified a putative receptor for A3*56. both in tissues from transgenic animals as well as in human brains. With this application, we propose to decipher the mechanism of action of Alphabeta*56 combining in vitro and in vivo paradigms. Finally we plan to evaluate whether Alphabeta oligomers including Alphabeta*56 represent the A3 entity(ies) connecting the two phenotypic hallmarks ofthe disease, namely amyloid plaques and neurofibrillary tangles.